bims-medebr 2024-01-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–01–21
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondrial Complex I Deficiency Masquerading as Stroke-Like Episode Clinically and as Alexander Disease Radiologically Following Chicken Pox.
Pyruvate Dehydrogenase Complex in Neonatal Hypoxic-Ischemic Brain Injury.
Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults.
Late pregnancy maternal naringin supplementation affects the mitochondria in the cerebellum of Wistar rat offspring via sirtuin 3 and AKT.
Glucose-derived glutamate drives neuronal terminal differentiation in vitro.
Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.
Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer's Disease Across Distinct Brain Regions.
Evidence of 13 C-lactate oxidation in the human brain from hyperpolarized 13 C-MRI.
Global Energy Metabolism Deficit in Alzheimer Disease Brain.
Transient synaptic enhancement triggered by exogenously supplied monocarboxylate in Drosophila motoneuron synapse.
Neurometabolic alterations in children and adolescents with functional neurological disorder.
Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology.
Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.
Circadian Regulation of the Lactate Metabolic Kinetics in Mice Using the [1H-13C]-NMR Technique.
Lactate protects neurons and astrocytes against ischemic injury by modulating Ca2+ homeostasis and inflammatory response.
Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.
Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction.
Mitochondrial dysfunction in neurodegenerative disorders.
Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder.
Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations.
A maternal high-fat diet during pregnancy and lactation induced depression-like behavior in offspring and myelin-related changes in the rat prefrontal cortex.
Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate.
The sphingosine-1-phosphate receptor 1 modulator ponesimod repairs cuprizone-induced demyelination and induces oligodendrocyte differentiation.
Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats.
Catalytic mechanism of trans-2-enoyl-CoA reductases in the fatty acid elongation cycle and its cooperative action with fatty acid elongases.

Ann Indian Acad Neurol. 2023 Nov-Dec;26(6):26(6): 977-979

Mitochondrial Complex I Deficiency Masquerading as Stroke-Like Episode Clinically and as Alexander Disease Radiologically Following Chicken Pox.

Vykuntaraju K Gowda, Arun Y Bylappa, Uddhav Kinhal, Varunvenkat M Srinivasan, Dhananjaya K Vamyanmane.

  Mitochondrial disorders are a group of metabolic disorders with variable presentation and usually affect organs with high energy requirements like the brain, eye, and heart. Seventeen-month-old girl child presented with right hemiparesis and regression of milestones following chicken pox. Investigations showed elevated lactate, white matter signal changes in both periventricular and subcortical white matter with frontal predominance in the MRI of the brain, cardiomyopathy in the echocardiography, with complex I deficiency in respiratory enzyme assay in the muscle biopsy. A homozygous missense variant c.304C>T (p. Arg102Cys) in exon 5 of NDUFS8 gene (chr11:67800682C>T; NM_002496.4) was detected on whole exome sequencing with positive parental Sanger for the same gene. The child was started on a mitochondrial cocktail, ramipril, and frusemide. Mitochondrial complex deficiency should be considered in cases with stroke-like episodes, and predominant white matter involvement on imaging mimicking classical genetic leukodystrophy like Alexander disease.

Keywords:  Alexander disease; India; NDUFS8 gene; mitochondrial disorder; stroke-like episodes

DOI:  https://doi.org/10.4103/aian.aian_339_23
ACS Pharmacol Transl Sci. 2024 Jan 12. 7(1): 42-47

Pyruvate Dehydrogenase Complex in Neonatal Hypoxic-Ischemic Brain Injury.

Tao Zhou, Yuangao Zhong, Yong Zhang, Yue Zhou.

The disruption of cerebral energy metabolism in relation to brain damage has been the subject of extensive research. However, the pyruvate dehydrogenase complex (PDHC), which is primarily characterized by poor cerebral energy metabolism following brain trauma, has received relatively little study in comparison to newborn hypoxic-ischemic brain injury. Mitochondrial PDHC, a multienzyme complex that functions as a crucial hub in energy metabolism and acts as a central metabolic node to mediate pyruvate oxidation after glycolysis and fuel the Krebs cycle to meet energy demands, has been reported to be one cause of energy metabolism dysfunction according to recent studies. Here we assess the potential mechanisms of neonatal hypoxic-ischemic brain injury-related brain dysfunction mediated by PDHC and further discuss the neuroprotective effects of therapeutic medicines that target PDHC activation. We also provide a summary of recent research on medicines that target PDHC in neonates with hypoxic-ischemic brain damage. Through an understanding of the mechanisms by which it is modulated and an investigation of the neuroprotective techniques available to activate brain PDHC and improve neonatal hypoxic-ischemic impairment, our review emphasizes the significance of PDHC impairment in neonatal hypoxic-ischemic brain injury.

DOI: https://doi.org/10.1021/acsptsci.3c00191
Geroscience. 2024 Jan 16.

Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults.

Francesca V Lopez, Andrew O'Shea, Zhiguang Huo, Steven T DeKosky, Theodore P Trouard, Gene E Alexander, Adam J Woods, Dawn Bowers.

  Aging is a major risk for cognitive decline and transition to dementia. One well-known age-related change involves decreased brain efficiency and energy production, mediated in part by changes in mitochondrial function. Damaged or dysfunctional mitochondria have been implicated in the pathogenesis of age-related neurodegenerative conditions like Alzheimer's disease (AD). The aim of the current study was to investigate mitochondrial function over frontal and temporal regions in a sample of 70 cognitively normal older adults with subjective memory complaints and a first-degree family history of AD. We hypothesized cerebral mitochondrial function and energy metabolism would be greater in temporal as compared to frontal regions based on the high energy consumption in the temporal lobes (i.e., hippocampus). To test this hypothesis, we used phosphorous (31P) magnetic resonance spectroscopy (MRS) which is a non-invasive and powerful method for investigating in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. We used a single voxel method (left temporal and bilateral prefrontal) to achieve optimal sensitivity. Results of separate repeated measures analyses of variance showed 31P MRS ratios of static energy, energy reserve, energy consumption, energy demand, and phospholipid membrane metabolism were greater in the left temporal than bilateral prefrontal voxels. Our findings that all 31P MRS ratios were greater in temporal than bifrontal regions support our hypothesis. Future studies are needed to determine whether findings are related to cognition in older adults.

Keywords:  Aging; Brain energy metabolism; Mitochondria; Phosphorus magnetic resonance spectroscopy

DOI:  https://doi.org/10.1007/s11357-023-01046-3
Int J Dev Neurosci. 2024 Jan 18.

Late pregnancy maternal naringin supplementation affects the mitochondria in the cerebellum of Wistar rat offspring via sirtuin 3 and AKT.

Bernardo Gindri Dos Santos, Pauline Maciel August, Débora Santos Rocha, Ismael Mesquita, Manuela Menegotto, Vinícius Stone, Cristiane Matté.

  Dietary polyphenol consumption is associated with a wide range of neuroprotective effects by improving mitochondrial function and signaling. Consequently, the use of polyphenol supplementation has been investigated as an approach to prevent neurodevelopmental diseases during gestation; however, the data obtained are still very inconclusive, mostly because of the difficulty of choosing the correct doses and period of administration to properly prevent neurodegenerative diseases without undermining normal brain development. Thus, we aimed to evaluate the effect of naringin supplementation during the third week of gestation on mitochondrial health and signaling in the cerebellum of 21-day-old offspring. The offspring born to naringin-supplemented dams displayed higher mitochondrial mass, membrane potential, and superoxide content in the cerebellum without protein oxidative damage. Such alterations were associated with dynamin-related protein 1 (DRP1) and phosphorylated AKT (p-AKT) downregulation, whereas the sirtuin 3 (SIRT3) levels were strongly upregulated. Our findings suggest that high dietary polyphenol supplementation during gestation may reduce mitochondrial fission and affect mitochondrial dynamics even 3 weeks after delivery via SIRT3 and p-AKT. Although the offspring born to naringin dams did not present neurobehavioral defects, the mitochondrial alterations elicited by naringin may potentially interfere during neurodevelopment and need to be further investigated.

Keywords:  brain; mitochondria; polyphenol; pregnancy

DOI:  https://doi.org/10.1002/jdn.10313
EMBO Rep. 2024 Jan 19.

Glucose-derived glutamate drives neuronal terminal differentiation in vitro.

Laura D'Andrea, Matteo Audano, Silvia Pedretti, Silvia Pelucchi, Ramona Stringhi, Gabriele Imperato, Giulia De Cesare, Clara Cambria, Marine H Laporte, Nicola Zamboni, Flavia Antonucci, Monica Di Luca, Nico Mitro, Elena Marcello.

  Neuronal maturation is the phase during which neurons acquire their final characteristics in terms of morphology, electrical activity, and metabolism. However, little is known about the metabolic pathways governing neuronal maturation. Here, we investigate the contribution of the main metabolic pathways, namely glucose, glutamine, and fatty acid oxidation, during the maturation of primary rat hippocampal neurons. Blunting glucose oxidation through the genetic and chemical inhibition of the mitochondrial pyruvate transporter reveals that this protein is critical for the production of glutamate, which is required for neuronal arborization, proper dendritic elongation, and spine formation. Glutamate supplementation in the early phase of differentiation restores morphological defects and synaptic function in mitochondrial pyruvate transporter-inhibited cells. Furthermore, the selective activation of metabotropic glutamate receptors restores the impairment of neuronal differentiation due to the reduced generation of glucose-derived glutamate and rescues synaptic local translation. Fatty acid oxidation does not impact neuronal maturation. Whereas glutamine metabolism is important for mitochondria, it is not for endogenous glutamate production. Our results provide insights into the role of glucose-derived glutamate as a key player in neuronal terminal differentiation.

Keywords:  Glutamate; Local Protein Translation in Neurons; Metabolism; Mitochondrial Pyruvate Carrier

DOI:  https://doi.org/10.1038/s44319-023-00048-8
Mol Neurobiol. 2024 Jan 15.

Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.

Mazyar Yazdani.

  Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. It is caused by mitochondrial DNA (mtDNA) rearrangements, mostly large-scale deletions of 1.1-10 kb. These deletions primarily affect energy supply through impaired oxidative phosphorylation and reduced ATP production. This impairment gives rise to dysfunction of several tissues, in particular those with high energy demand like brain and muscles. Over the past decades, changes in respiratory chain complexes and energy metabolism have been emphasized, whereas little attention has been paid to other reports on ROS overproduction, protein synthesis inhibition, myelin vacuolation, demyelination, autophagy, apoptosis, and involvement of lipid raft and oligodendrocytes in KSS. Therefore, this paper draws attention towards these relatively underemphasized findings that might further clarify the pathologic cascades following deletions in the mtDNA.

Keywords:  Apoptosis; Autophagy; Lipid raft; Myelin Vacuolation; Oligodendrocyte; Reactive Oxygen Species (ROS)

DOI:  https://doi.org/10.1007/s12035-024-03938-7
J Proteome Res. 2024 Jan 18.

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer's Disease Across Distinct Brain Regions.

Melanie T Odenkirk, Xueyun Zheng, Jennifer E Kyle, Kelly G Stratton, Carrie D Nicora, Kent J Bloodsworth, Catriona A Mclean, Colin L Masters, Matthew E Monroe, James D Doecke, Richard D Smith, Kristin E Burnum-Johnson, Blaine R Roberts, Erin S Baker.

  Alzheimer's disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4- for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.

Keywords:  Alzheimer’s disease; apolipoprotein E (APOE); lipidomics; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.3c00604
Magn Reson Med. 2024 Jan 17.

Evidence of 13 C-lactate oxidation in the human brain from hyperpolarized 13 C-MRI.

Biranavan Uthayakumar, Hany Soliman, Albert P Chen, Nadia Bragagnolo, Nicole I C Cappelletto, Ruby Endre, William J Perks, Nathan Ma, Chris Heyn, Kayvan R Keshari, Charles H Cunningham.

   PURPOSE: To test the hypothesis that lactate oxidation contributes to the 13$$ {}^{13} $$ C-bicarbonate signal observed in the awake human brain using hyperpolarized 13$$ {}^{13} $$ C MRI.
METHODS: Healthy human volunteers (N = 6) were scanned twice using hyperpolarized 13$$ {}^{13} $$ C-MRI, with increased radiofrequency saturation of 13$$ {}^{13} $$ C-lactate on one set of scans. 13$$ {}^{13} $$ C-lactate, 13$$ {}^{13} $$ C-bicarbonate, and 13$$ {}^{13} $$ C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test.
RESULTS: Increased 13$$ {}^{13} $$ C-lactate radiofrequency saturation resulted in a significantly lower 13$$ {}^{13} $$ C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions.
CONCLUSION: Radiofrequency saturation of 13$$ {}^{13} $$ C-lactate leads to a decrease in 13$$ {}^{13} $$ C-bicarbonate signal, demonstrating that the 13$$ {}^{13} $$ C-lactate generated from the injected 13$$ {}^{13} $$ C-pyruvate is being converted back to 13$$ {}^{13} $$ C-pyruvate and oxidized throughout the human brain.

Keywords:  biochemistry; brain; neurological; normal

DOI:  https://doi.org/10.1002/mrm.29919
J Prev Alzheimers Dis. 2024 ;11(1): 171-178

Global Energy Metabolism Deficit in Alzheimer Disease Brain.

V Patel, J Mill, O C Okonkwo, S Salamat, L Li, T Raife.

   BACKGROUND: The understanding of Alzheimer's disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism.
OBJECTIVES: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control.
DESIGN, SETTING, AND PARTICIPANTS: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval. Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®.
RESULTS: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body β-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain.
CONCLUSION: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.

Keywords:  Alzheimer disease; beta-hydroxybutyrate; energy metabolism deficits; ketone body; metabolomics

DOI:  https://doi.org/10.14283/jpad.2023.91
Neuroscience. 2024 Jan 12. pii: S0306-4522(24)00011-3. [Epub ahead of print]

Transient synaptic enhancement triggered by exogenously supplied monocarboxylate in Drosophila motoneuron synapse.

María-Graciela Delgado, Ricardo Delgado.

  Current evidence suggests that glial cells provide C3 carbon sources to fuel neuronal activity; however, this notion has become challenged by biosensor studies carried out in acute brain slices or in vivo, showing that neuronal activity does not rely on the import of astrocyte-produced L-lactate. Rather, stimulated neurons become net lactate exporters, as it was also shown in Drosophila neurons, in which astrocyte-provided lactate returns as lipid droplets to be stored in glial cells. In this view, we investigate whether exogenously supplied monocarboxylates can support Drosophila motoneuron neurotransmitter release (NTR). By assessing the excitatory post-synaptic current (EPSC) amplitude under voltage-clamp as NTR indicative, we found that both pyruvate and L-lactate, as the only carbon sources in the synapses bathing-solution, cause a large transient NTR enhancement, which declines to reach a synaptic depression state, from which the synapses do not recover. The FM1-43 pre-synaptic loading ability, however, is maintained under monocarboxylate, suggesting that SV cycling should not contribute to the synaptic depression state. The NTR recovery was reached by supplementing the monocarboxylate medium with sucrose. However, monocarboxylate addition to sucrose medium does not enhance NTR, but it does when the disaccharide concentration becomes too reduced. Thus, when pyruvate concentrations become too reduced, exogenously supplied L-lactate could be converted to pyruvate and metabolized by the neural mitochondria, triggering the NTR enhancement. Significance Statement The question of whether monocarboxylic acids can fuel the Drosophila motoneuron NTR was challenged. Our findings show that exogenously supplied monocarboxylates trigger a large transient synaptic enhancement just under extreme glycolysis reduction but fail to maintain NTR under sustained synaptic demand, still at low frequency stimulation, driven to the synapses to a synaptic depression state. Glycolysis activation, by adding sucrose to the monocarboxylate bath solution, restores the motoneuron NTR ability, giving place to a hexoses role in SV recruitment. Moreover these results suggest exogenously supplied C3 carbon sources could have an additional role beyond providing energetic support for neural activity.

Keywords:  Drosophila motoneuron synapses; Monocarboxylic acids; Neurotransmitter release; Synaptic vesicles

DOI:  https://doi.org/10.1016/j.neuroscience.2024.01.003
Neuroimage Clin. 2023 Dec 21. pii: S2213-1582(23)00248-6. [Epub ahead of print]41 103557

Neurometabolic alterations in children and adolescents with functional neurological disorder.

Molly Charney, Sheryl Foster, Vishwa Shukla, Wufan Zhao, Sam H Jiang, Kasia Kozlowska, Alexander Lin.

   OBJECTIVES: In vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included N-acetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined.
METHODS: MRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point-resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest.
RESULTS: In the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures-a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN.
CONCLUSIONS: Our findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Keywords:  Excitatory/inhibitory neurotransmitters; Functional neurological disorder; Functional seizures; MEGAPRESS; Magnetic resonance spectroscopy; Neurometabolite

DOI:  https://doi.org/10.1016/j.nicl.2023.103557
Front Physiol. 2023 ;14 1229108

Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology.

Rama Jamjoum, Saurav Majumder, Batoul Issleny, Johnny Stiban.

  Metabolic pathways are complex and intertwined. Deficiencies in one or more enzymes in a given pathway are directly linked with genetic diseases, most of them having devastating manifestations. The metabolic pathways undertaken by sphingolipids are diverse and elaborate with ceramide species serving as the hubs of sphingolipid intermediary metabolism and function. Sphingolipids are bioactive lipids that serve a multitude of cellular functions. Being pleiotropic in function, deficiency or overproduction of certain sphingolipids is associated with many genetic and chronic diseases. In this up-to-date review article, we strive to gather recent scientific evidence about sphingolipid metabolism, its enzymes, and regulation. We shed light on the importance of sphingolipid metabolism in a variety of genetic diseases and in nervous and immune system ailments. This is a comprehensive review of the state of the field of sphingolipid biochemistry.

Keywords:  ceramide; inhibitors; metabolic interrelationships; metabolism; pathophysiology; physiology; sphingolipids

DOI:  https://doi.org/10.3389/fphys.2023.1229108
J Cell Biochem. 2024 Jan 16.

Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.

Peng Zhou, Zhe-Cheng Yu, Cong Cao, Huai-Rui Cui, Mao-Chao Ding, Chao-Xian Yang, Min Liao.

  Pro-inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro-inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF-κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF-κB regulated pro-inflammatory response of microglia induced by low glucose.

Keywords:  MCT1; microglia; pro-inflammatory; pyruvate; stroke

DOI:  https://doi.org/10.1002/jcb.30524
Mol Neurobiol. 2024 Jan 17.

Circadian Regulation of the Lactate Metabolic Kinetics in Mice Using the [1H-13C]-NMR Technique.

Lili Chen, Kefan Wu, Jingang He, Jiabao Hou, Yuan Zhang, Lian Liu, Jie Wang, Zhongyuan Xia.

  Lactate is not only the energy substrate of neural cells, but also an important signal molecule in brain. In modern societies, disturbed circadian rhythms pose a global challenge. Therefore, exploring the influence of circadian period on lactate and its metabolic kinetics is essential for the advancement of neuroscientific research. In the present study, the different groups of mice (L: 8:00 a.m.; D: 20:00 p.m.; SD: 20:00 p.m. with 12 h acute sleep deprivation) were infused with [3-13C] lactate through the lateral tail vein for a duration of 2 min. After 30-min lactate metabolism, the animals were euthanized and the tissues of brain and liver were obtained and extracted, and then, the [1H-13C] NMR technology was employed to investigate the kinetic information of lactate metabolism in different brain regions and liver to detect the enrichment of various metabolic kinetic information. Results revealed the fluctuating lactate concentrations in the brain throughout the day, with lower levels during light periods and higher levels during dark periods. Most metabolites displayed strong sensitivity to circadian rhythm, exhibiting significant day-night variations. Conversely, only a few metabolites showed changes after acute sleep deprivation, primarily in the temporal brain region. Interestingly, in contrast to brain lactate metabolism, liver lactate metabolism exhibited a significant increase following acute sleep deprivation. This study explored the kinetics of lactate metabolism, hinted at potential clinical implications for disorders involving circadian rhythm disturbances, and providing a new research basis for clinical exploration of brain and liver lactate metabolism.

Keywords:  Brain; Circadian; Lactate; Liver; Metabolic kinetics; Proton observed carbon editing (POCE)

DOI:  https://doi.org/10.1007/s12035-024-03927-w
FEBS J. 2024 Jan 16.

Lactate protects neurons and astrocytes against ischemic injury by modulating Ca2+ homeostasis and inflammatory response.

Valentina A Babenko, Elena G Varlamova, Aleena A Saidova, Egor A Turovsky, Egor Y Plotnikov.

  Lactate is now considered an additional fuel or signaling molecule in the brain. In this study, using an oxygen-glucose deprivation (OGD) model, we found that treatment with lactate inhibited the global increase in intracellular calcium ion concentration ([Ca2+ ]) in neurons and astrocytes, decreased the percentage of dying cells, and caused a metabolic shift in astrocytes and neurons toward aerobic oxidation of substrates. OGD resulted in proinflammatory changes and increased expression of cytokines and chemokines, whereas incubation with lactate reduced these changes. Pure astrocyte cultures were less sensitive than neuroglia cultures during OGD. Astrocytes exposed to lipopolysaccharide (LPS) also showed pro-inflammatory changes that were reduced by incubation with lactate. Our study suggests that lactate may have neuroprotective effects under ischemic and inflammatory conditions.

Keywords:  astrocytes; energy metabolism; ischemia; lactate; neurons; neuroprotection

DOI:  https://doi.org/10.1111/febs.17051
Brain. 2024 Jan 18. pii: awae018. [Epub ahead of print]

Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.

Mikel Muñoz-Oreja, Abigail Sandoval, Ove Bruland, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Marina Villar-Fernandez, Haizea Hernández-Eguiazu, Ixiar Hernández, Yohan Park, Leire Goicoechea, Nerea Pascual-Frías, Carmen Garcia-Ruiz, Jose Fernandez-Checa, Itxaso Martí-Carrera, Francisco Javier Gil-Bea, Mazahir T Hasan, Matthew E Gegg, Cecilie Bredrup, Per-Morten Knappskog, Gorka Gereñu-Lopetegui, Kristin N Varhaug, Laurence A Bindoff, Antonella Spinazzola, Wan Hee Yoon, Ian J Holt.

  Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, nor were the effects on cell membranes or the wider cell known. Using patient-derived cells we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. Using nutrient restriction and cholesterol supplementation, we show that the Drosophila Atad3 mutant displays heightened cholesterol dependence. Collectively, these findings suggest elevated cholesterol enhances tolerance to pathological ATAD3 variants, at a cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.

Keywords:  AAA+ ATPase; ATAD3; cholesterol disorders; lysosomal storage disorders; lysosomes; mitochondrial disease

DOI:  https://doi.org/10.1093/brain/awae018
PLoS One. 2024 ;19(1): e0296790

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction.

Jean-Baptiste Pérot, Anna Niewiadomska-Cimicka, Emmanuel Brouillet, Yvon Trottier, Julien Flament.

SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.

DOI: https://doi.org/10.1371/journal.pone.0296790
Neurotherapeutics. 2023 Dec 19. pii: S1878-7479(23)01900-1. [Epub ahead of print]21(1): e00292

Mitochondrial dysfunction in neurodegenerative disorders.

Madelyn M Klemmensen, Seth H Borrowman, Colin Pearce, Benjamin Pyles, Bharatendu Chandra.

  Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.

Keywords:  Aging; Bioenergetics; Mitochondria; Neurodegeneration; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.neurot.2023.10.002
Neurosci Bull. 2024 Jan 16.

Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder.

Man Chen, Yun-Hui Chu, Wen-Xiang Yu, Yun-Fan You, Yue Tang, Xiao-Wei Pang, Hang Zhang, Ke Shang, Gang Deng, Luo-Qi Zhou, Sheng Yang, Wei Wang, Jun Xiao, Dai-Shi Tian, Chuan Qin.

  Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.

Keywords:  Low-density lipoprotein; Microglia; Neuromyelitis optica spectrum disorder

DOI:  https://doi.org/10.1007/s12264-023-01166-y
Acta Naturae. 2023 Oct-Dec;15(4):15(4): 4-22

Animal Models of Mitochondrial Diseases Associated with Nuclear Gene Mutations.

O A Averina, S A Kuznetsova, O A Permyakov, P V Sergiev.

  Mitochondrial diseases (MDs) associated with nuclear gene mutations are part of a large group of inherited diseases caused by the suppression of energy metabolism. These diseases are of particular interest, because nuclear genes encode not only most of the structural proteins of the oxidative phosphorylation system (OXPHOS), but also all the proteins involved in the OXPHOS protein import from the cytoplasm and their assembly in mitochondria. Defects in any of these proteins can lead to functional impairment of the respiratory chain, including dysfunction of complex I that plays a central role in cellular respiration and oxidative phosphorylation, which is the most common cause of mitopathologies. Mitochondrial diseases are characterized by an early age of onset and a progressive course and affect primarily energy-consuming tissues and organs. The treatment of MDs should be initiated as soon as possible, but the diagnosis of mitopathologies is extremely difficult because of their heterogeneity and overlapping clinical features. The molecular pathogenesis of mitochondrial diseases is investigated using animal models: i.e. animals carrying mutations causing MD symptoms in humans. The use of mutant animal models opens new opportunities in the study of genes encoding mitochondrial proteins, as well as the molecular mechanisms of mitopathology development, which is necessary for improving diagnosis and developing approaches to drug therapy. In this review, we present the most recent information on mitochondrial diseases associated with nuclear gene mutations and animal models developed to investigate them.

Keywords:  animal models; mitochondrial diseases; mutations; nDNA

DOI:  https://doi.org/10.32607/actanaturae.25442
Front Mol Neurosci. 2023 ;16 1303718

A maternal high-fat diet during pregnancy and lactation induced depression-like behavior in offspring and myelin-related changes in the rat prefrontal cortex.

Małgorzata Frankowska, Paulina Surówka, Kinga Gawlińska, Małgorzata Borczyk, Michał Korostyński, Małgorzata Filip, Irena Smaga.

  In accordance with the developmental origins of health and disease, early-life environmental exposures, such as maternal diet, can enhance the probability and gravity of health concerns in their offspring in the future. Over the past few years, compelling evidence has emerged suggesting that prenatal exposure to a maternal high-fat diet (HFD) could trigger neuropsychiatric disorders in the offspring, such as depression. The majority of brain development takes place before birth and during lactation. Nevertheless, our understanding of the impact of HFD on myelination in the offspring's brain during both gestation and lactation remains limited. In the present study, we investigated the effects of maternal HFD (60% energy from fat) on depressive-like and myelin-related changes in adolescent and adult rat offspring. Maternal HFD increased immobility time during the forced swimming test in both adolescent and adult offspring. Correspondingly, the depressive-like phenotype in offspring correlated with dysregulation of several genes and proteins in the prefrontal cortex, especially of myelin-oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), kallikrein 6, and transferrin in male offspring, as well as of MOG and kallikrein 6 in female offspring, which persist even into adulthood. Maternal HFD also induced long-lasting adaptations manifested by the reduction of immature and mature oligodendrocytes in the prefrontal cortex in adult offspring. In summary, maternal HFD-induced changes in myelin-related genes are correlated with depressive-like behavior in adolescent offspring, which persists even to adulthood.

Keywords:  depression; high-fat diet; maternal diet; myelination; offspring

DOI:  https://doi.org/10.3389/fnmol.2023.1303718
Nat Commun. 2024 Jan 17. 15(1): 490

Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate.

Mackenzie E Smith, Chuck T Chen, Chiraag A Gohel, Giulia Cisbani, Daniel K Chen, Kimia Rezaei, Andrew McCutcheon, Richard P Bazinet.

Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL), primarily, from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results in adults. In this work, we use naturally occurring carbon isotope ratios (13C/12C; δ13C) to uncover the origin of brain PAM at postnatal days 0, 10, 21 and 35, and RNA sequencing to identify the pathways involved in maintaining brain PAM, at day 35, in mice fed diets with low, medium, and high PAM from birth. Here we show that DNL from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM. Importantly, the upregulation of hepatic DNL genes, in response to low PAM at day 35, demonstrates the presence of a compensatory mechanism to maintain total brain PAM pools compared to the liver; suggesting the importance of brain PAM regulation.

DOI: https://doi.org/10.1038/s41467-023-44388-4
FASEB J. 2024 Jan 31. 38(2): e23413

The sphingosine-1-phosphate receptor 1 modulator ponesimod repairs cuprizone-induced demyelination and induces oligodendrocyte differentiation.

Emily Willems, Melissa Schepers, Elisabeth Piccart, Esther Wolfs, Niels Hellings, Maria Ait-Tihyaty, Tim Vanmierlo.

  Sphingosine-1-phosphate receptor (S1PR) modulators are clinically used to treat relapse-remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα-coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone-induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro.

Keywords:  cuprizone; multiple sclerosis; oligodendrocyte precursor; remyelination; visual evoked potentials

DOI:  https://doi.org/10.1096/fj.202301557RR
Curr Res Neurobiol. 2024 ;6 100123

Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats.

Chirag P Talati, Jonathan W Lee, Silu Lu, Norma B Ojeda, Varsha Prakash, Nilesh Dankhara, Tanner C Nielson, Sara P Sandifer, Gene L Bidwell, Yi Pang, Lir-Wan Fan, Abhay J Bhatt.

  There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.

Keywords:  Hypoxia-ischemia; Intranasal insulin; Neuron apoptosis; Neuroprotection; Sensorimotor dysfunction

DOI:  https://doi.org/10.1016/j.crneur.2023.100123
J Biol Chem. 2024 Jan 13. pii: S0021-9258(24)00032-2. [Epub ahead of print] 105656

Catalytic mechanism of trans-2-enoyl-CoA reductases in the fatty acid elongation cycle and its cooperative action with fatty acid elongases.

Ryoya Kato, Yuka Takenaka, Yusuke Ohno, Akio Kihara.

  The fatty acid (FA) elongation cycle produces very-long-chain FAs with ≥C21, which have unique physiological functions. Trans-2-enoyl-CoA reductases (yeast, Tsc13; mammals, TECR) catalyze the reduction reactions in the fourth step of the FA elongation cycle and in the sphingosine degradation pathway. However, their catalytic residues and coordinated action in the FA elongation cycle complex are unknown. To reveal these, we generated and analyzed Ala-substituted mutants of 15 residues of Tsc13. An in vitro FA elongation assay showed that nine of these mutants were less active than WT protein, with E91A and Y256A being the least active. Growth complementation analysis, measurement of ceramide levels, and deuterium-sphingosine labeling revealed that the function of the E91A mutant was substantially impaired in vivo. In addition, we found that the activity of FA elongases, which catalyze the first step of the FA elongation cycle, were reduced in the absence of Tsc13. Similar results were observed in Tsc13 E91A-expressing cells, which is attributable to reduced interaction between the Tsc13 E91A mutant and the FA elongases Elo2/Elo3. Finally, we found that E94A and Y248A mutants of human TECR, which correspond to E91A and Y256A mutants of Tsc13, showed reduced and almost no activity, respectively. Based on these results and the predicted three-dimensional structure of Tsc13, we speculate that Tyr256/Tyr248 of Tsc13/TECR is the catalytic residue that supplies a proton to trans-2-enoyl-CoAs. Our findings provide a clue concerning the catalytic mechanism of Tsc13/TECR and the coordinated action in the FA elongation cycle complex.

Keywords:  ceramide; enzyme catalysis; fatty acid; fatty acid elongation cycle; fatty acid metabolism; lipid; sphingolipid; trans-2-enoyl-CoA reductase; very-long-chain fatty acid; yeast

DOI:  https://doi.org/10.1016/j.jbc.2024.105656